The invention relates to substituted N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives, their production and use as pharmaceutical agents for treating various diseases.
Known from DE 198 54 081 A1 or WO 00/31066 are substituted N-pyrazolyl-phenoxynicotinic acid-(thio)amides that are used as herbicides. These compounds clearly differ structurally from the compounds according to the invention, however.
From WO 01/12189, 3(5)-amino-pyrazole derivatives and their use as pharmaceutical agents, especially for treating cancer and cell-proliferative diseases, are known. These compounds also differ from the compounds according to the invention by their structure, especially on the pyrazole ring.
There is still a great need for effective pharmaceutical agents for treating cancer and other cell-proliferative diseases.
It has now been found that compounds of general formula I 
in which
R1 stands for linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy, C1-C6-alkylthio or C3-C12-cycloalkyl, C3-C12-cycloalkenyl, C3-C12-heterocycloalkyl, C3-C12-heterocycloalkenyl, aryl or heteroaryl, which optionally can be substituted in one or more places in the same way or differently,
R2 and R3 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently,
R4 and R5 are the same or different and stand for hydrogen, halogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal with O,O; N,O; O,S; or S,S, which optionally can be substituted with C1-C6-alkyl, or
R2 and R4 together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently,
R6 and R7 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkinyl, which optionally can be substituted in one or more places in the same way or differently, or together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently, or
R5 and R6 optionally together form a double bond, or
R5 and R6 together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently,
T stands for xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x95x90CH2xe2x80x94, xe2x80x94CHxe2x89xa1CHxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x95x90CO, and
n stands for 0-6, as well as tautomers, isomers and salts thereof.
Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl.
Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, isopentyloxy or hexyloxy.
Alkythio is defined in each case as a straight-chain or branched alkylthio radical, such as, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio or hexylthio.
Cycloalkyls are defined as monocyclic alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings or tricyclic rings, such as, for example, norbornyl, adamantanyl, etc.
Cycloalkenyl is defined in each case as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, whereby the linkage can be carried out both to the double bond and to the single bonds.
Halogen is defined in each case as fluorine, chlorine, bromine or iodine.
Alkenyl is defined in each case as a straight-chain or branched alkenyl radical that contains 2-6, preferably 2-4, C atoms. For example, the following radicals can be mentioned: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, and allyl.
Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4, C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.
The aryl radical in each case comprises 3-12 carbon atoms, and can be benzocondensed in each case.
For example, there can be mentioned: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc.
The heteroaryl radical in each case comprises 3-16 ring atoms, and instead of carbon, the radical can contain one or more heteroatoms that are the same or different, such as oxygen, nitrogen or sulfur in the ring, and can be monocyclic, bicyclic or tricyclic, and in addition in each case can be benzocondensed.
For example, there can be mentioned:
Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc. and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as, e.g., quinolyl, isoquinolyl, etc.; or oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, etc. and benzo derivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, etc.
Heterocycloalkyl stands for an alkyl ring that comprises 3-12 carbon atoms and that instead of carbon contains one or more heteoratoms that are the same or different, such as, e.g., oxygen, sulfur or nitrogen.
As heterocycloalkyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.
Heterocycloalkenyl stands for an alkyl ring that comprises 3-12 carbon atoms and that instead of carbon contains one or more heteroatoms that are the same or different, such as, e.g., oxygen, sulfur or nitrogen, and that is partially saturated.
As heterocycloalkenyls, there can be mentioned, e.g.: pyran, thiine, dihydroazete, etc.
Cyclic acetal stands for a ring, such as, e.g., 
which optionally can be substituted with a C1-C6-alkyl group.
The aryl radical and the heteroaryl radical can be substituted in each case in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkoxycarbonyl, cyano, nitro, C1-6-alkylsulfanyl, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, or with the group xe2x80x94C(O) C1-6-alkyl, xe2x80x94NHC1-6-alkyl, xe2x80x94N-di-C1-6-alkyl, xe2x80x94CONH2, xe2x80x94CONHC1-6-alkyl or xe2x80x94CON-di-C1-6-alkyl, or can be substituted with another aryl or heteroaryl radical, which optionally itself can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkoxycarbonyl, cyano, nitro, C1-6-alkylcarbonyl, C1-6-alkylsulfanyl, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, or with the group xe2x80x94C(O)C1-6-alkyl, xe2x80x94NHC1-6-alkyl, xe2x80x94N-di-C1-6-alkyl, xe2x80x94CONH2, xe2x80x94CONHC1-6-alkyl or xe2x80x94CON-di-C1-6-alkyl.
If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali salts and alkaline-earth salts as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and 1-amino-2,3,4-butanetriol.
If a basic group is included, the physiologically compatible salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, i.a.
Those compounds of general formula I, in which
R1 stands for linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy, C1-C6-alkylthio or C3-C12-cycloalkyl, C3-C12-cycloalkenyl, C3-C12-heterocycloalkyl, C3-C12-heterocycloalkenyl, aryl or heteroaryl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkoxycarbonyl, cyano, nitro, C1-6-alkylsulfinyl, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, or with the group xe2x80x94C(O)C1-6-alkyl, xe2x80x94NHC1-6-alkyl, xe2x80x94N-di-C1-6-alkyl, xe2x80x94CONH2, xe2x80x94CONHC1-6-alkyl or xe2x80x94CON-di-C1-6-alkyl, or can be substituted with another aryl radical or heteroaryl radical that optionally itself can be substituted in one or more places in the same way or differently,
R2 and R3 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl,
R4 and R5 are the same or different and stand for hydrogen, halogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal of the structure 
R2 and R4 together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or
R3 and R5 together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl,
R6 and R7 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkinyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or
R5 and R6 optionally together form a double bond,
T stands for xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x95x90CH2xe2x80x94, xe2x80x94CHxe2x89xa1CHxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x95x90CO, and
n stands for 0-6, as well as tautomers, isomers and salts thereof, have proven especially valuable.
Those compounds of general formula I, in which
R1 stands for linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy, C1-C6-alkylthio or C3-C12-cycloalkyl, C3-C12-cycloalkenyl, C3-C12-heterocycloalkyl, C3-C12-heterocycloalkenyl, aryl or heteroaryl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkoxycarbonyl, cyano, nitro, C1-6-alkylsulfanyl, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, or with the group xe2x80x94C(O)C1-6-alkyl, xe2x80x94NHC1-6-alkyl, xe2x80x94N-di-C1-6-alkyl, xe2x80x94CONH2, xe2x80x94CONHC1-6-alkyl or xe2x80x94CON-di-C1-6-alkyl, or can be substituted with another aryl or heteroaryl radical, which optionally itself can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkoxycarbonyl, cyano, nitro, C1-6-alkylcarbonyl, C1-6-alkylsulfanyl, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, or with the group xe2x80x94C(O)C1-6-alkyl, xe2x80x94NHC1-6-alkyl, xe2x80x94N-di-C1-6-alkyl, xe2x80x94CONH2, xe2x80x94CONHC1-6-alkyl or xe2x80x94CON-di-C1-6-alkyl,
R2 and R3 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl,
R4 and R5 are the same or different and stand for hydrogen, halogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal of the structure 
R2 and R4 together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or
R3 and R5 together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl,
R6 and R7 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkinyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or together form a C3-C12-cycloalkyl ring or a C3-C12-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or
R5 and R6 optionally together form a double bond,
T stands for xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x95x90CH2xe2x80x94, xe2x80x94CHxe2x89xa1CHxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x95x90CO, and
n stands for 0-6, as well as tautomers, isomers and salts thereof, have proven quite especially valuable.
Those compounds of general formula I, in which
R1 stands for linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C1-C6-alkoxy, C1-C6-alkylthio or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, thiinyl, dihydroazetyl, cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, azulenyl, fluorenyl, anthracenyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzofuranyl, benzothienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, 1,3-benzodioxol-5-yl, phenoxazinyl or xanthenyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C6-alkyl, C1-16-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkoxycarbonyl, cyano, nitro, C1-6-alkylsulfanyl, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, or can be substituted with the group xe2x80x94C(O)C1-6-alkyl, xe2x80x94NHC1-6-alkyl, xe2x80x94N-di-C1-6-alkyl, xe2x80x94CONH2, xe2x80x94CONHC1-6-alkyl or xe2x80x94CON-di-C1-6-alkyl, or can be substituted with another aryl or heteroaryl radical, which optionally itself can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkoxycarbonyl, cyano, nitro, C1-6-alkylcarbonyl, C1-6-alkylsulfanyl, C1-6-alkylsulfinyl, C1-6-alkylsulfonyl, or with the group xe2x80x94C(O)C1-6-alkyl, xe2x80x94NHC1-6-alkyl, xe2x80x94N-di-C1-6-alkyl, xe2x80x94CONH2, xe2x80x94CONHC1-6-alkyl or xe2x80x94CON-di-C1-6-alkyl,
R2 and R3 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl,
R4 and R5 are the same or different and stand for hydrogen, halogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl or C1-C6-alkoxy, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or together stand for a carbonyl group, or together form a cyclic five- or six-ring-acetal of the structure 
R2 and R4 together form a C3-C7-cycloalkyl ring or a C3-C7-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or
R3 and R5 together form a C3-C7-cycloalkyl ring or a C3-C7-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way of differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl,
R6 and R7 are the same or different and stand for hydrogen, linear or branched C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkinyl, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or together form a C3-C7-cycloalkyl ring or a C3-C7-cycloalkenyl ring, which optionally can be substituted in one or more places in the same way or differently with hydroxy, halogen, amino, C1-6-alkoxy, or with the group xe2x80x94NHC1-6-alkyl or xe2x80x94N-di-C1-6-alkyl, or
R5 and R6 optionally together form a double bond,
T stands for xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x95x90CH2xe2x80x94, xe2x80x94CHxe2x89xa1CHxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x95x90CO, and
n stands for 0-6, as well as tautomers, isomers and salts thereof, are especially valuable.
Selected compounds are those compounds of general formula I, in which
R1 stands for C1-C6-alkylthio, phenyl, biphenyl, thienyl, cyclopropyl, cyclohexyl, pyridyl, naphthyl, 1,3-benzodioxol-5-yl or isoxazolyl, which optionally can be substituted in one or more places in the same way or differently with halogen, amino, cyano, C1-6-alkyl-sulfonyl, C1-6-alkyl, halo-C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, or with the group xe2x80x94C(O)C1-6-alkyl, or which can be substituted with phenyl, thienyl, naphthyl, pyridyl, furanyl or pyrimidinyl, which optionally itself can be substituted in one or more places in the same way or differently with C1-6-alkyl, C1-6-alkoxy, amino, C1-6-alkylsulfonyl, cyano or with the group xe2x80x94C(O)NH2,
R2, R3, R4, R5, R6 and R7 stand for hydrogen or C1-6-alkyl,
T stands for the group xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Oxe2x80x94, and
n stands for 0-2, as well as tautomers, isomers and salts thereof.
The production of the compounds of general formula I according to the invention is preferably carried out by
a) a 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of general formula II 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I,
being reacted with a compound of general formula III
R1xe2x80x94COXxe2x80x83xe2x80x83(III),
in which R1 has the meaning that is indicated in general formula I, and X stands for hydroxy, fluorine, chlorine, bromine or a leaving group,
xe2x80x83to form compounds of general formulas IVa and IVb 
in which R1 has the meaning that is indicated in general formula I, which then are hydrolyzed selectively under basic conditions to form the compounds of general formula I, or
b) a 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of general formula II 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I,
being reacted with a compound of general formula V
R1xe2x80x94COxe2x80x94CCl3xe2x80x83xe2x80x83(V),
in which R1 has the meaning that is indicated in general formula I, to form a compound of general formula I, or
c) if R1 stands for a 4-halophenylacetyl radical in the meaning of general formula I, a compound of general formulas VI or VI a 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I, 
stands for a solid phase and Y stands for bromine or iodine, being reacted under the conditions of a Suzuki reaction with a boronic acid of general formula VII 
in which R8 stands for aryl or heteroaryl, to form a compound of general formula Ia or Ib, 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I, R8 stands for aryl or heteroaryl, and 
means a solid phase, whereby in the case of the compound that is bonded to a solid phase, the cleavage is carried out by acid hydrolysis, or
d) a compound of general formula VI or VIa, in which R1 stands for a 4-halophenylacetyl radical, 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I, 
means a solid phase, and Y stands for bromine or iodine, being reacted under the conditions of a Miyaura reaction with a diboronic acid derivative of general formula VIII 
to form compounds of general formulas IX or IX a 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I, and 
means a solid phase, and then the compounds of general formulas IX and IXa being reacted with a compound of general formula X,
R9Zxe2x80x83xe2x80x83(X),
in which R9 stands for aryl or heteroaryl and Z stands for bromine or iodine, to form compounds of general formulas Ic or Id 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I, 
means a solid phase, and R9 stands for aryl or heteroaryl, and in the case of the compound that is bonded to a solid phase, the cleavage is carried out by acidic hydrolysis, or
e) a compound of general formula XI 
in which R1 has the meanings that are indicated in general formula I, being reacted with N-(1-cyclopenten-1-yl)-morpholine of general formula XII 
to form compounds of general formula XIII 
in which R1 has the meanings that are indicated in general formula I, and then the compounds of general formula XIII being cyclized with hydrazine to compounds of formula I, or
f) a compound of general formula XIV, 
in which X stands for oxygen or sulfur, being reacted with a compound of general formula XV in the presence of strong bases (e.g., lithium diisopropylamide),
R1xe2x80x94COOR10xe2x80x83xe2x80x83(XV),
in which R1 has the meaning that is indicated in general formula I, and R10 stands for C1-C6-alkyl, to form a compound of general formula I.
Process Variant a)
The reaction of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of formula II with a compound of formula III can be carried out in the presence of a base such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine or pyridine in a suitable solvent, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide at a temperature of between 0xc2x0 C. and the boiling point of the solvent. One of the methods, known from peptide chemistry, for forming amides can also be used.
The reaction of a compound of general formula IVa and IVb to form a compound of formula I can be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium methylate in a suitable solvent, such as methanol, ethanol or a mixture that consists of methanol or ethanol with water at room temperature.
Process Variant b)
The reaction of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of formula II with a compound of formula V to form a compound of formula I can be carried out in the presence of a base such as triethylamine, N-methylmorpholine, N,N-diisopropyl ethylamine in a suitable solvent, such as tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamide at a temperature of between room temperature and the boiling point of the solvent.
Process Variant c)
The Suzuki reaction of a compound of formula VI with a boronic acid of formula VII can be carried out in the presence of a base such as cesium fluoride, sodium carbonate or potassium carbonate and a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, or Pd(OAc)2/PPh3 in a suitable solvent such as dioxane, tetrahydrofuran, dimethoxyethane or a mixture that consists of methanol and dimethoxyethane at a temperature of between room temperature and the boiling point of the solvent.
Process Variant d)
The Miyaura reaction of a compound of formula VI with a diboronic acid derivative of formula VIII to form a compound of formula IX can be carried out in the presence of a base, such as potassium acetate or triethylamine and a catalyst such as PdCl2 (diphenylphosphinoferrocene) or PdCl2(PPh3)2 in a suitable solvent such as acetonitrile, dioxane, dimethoxyethane, dimethyl sulfoxide or N,N-dimethylformamide at a temperature of between room temperature and the boiling point of the solvent.
The reaction of a compound of formula IX with a compound of formula X can be carried out in the presence of a base such as sodium carbonate, potassium carbonate or potassium phosphate and a catalyst such as Pd(PPh3)4 or PdCl2(PPh3)2 in a suitable solvent such as dioxane, tetrahydrofuran, dimethoxyethane or N,N-dimethylformamide at a temperature of between room temperature and the boiling point of the solvent.
Process Variant e)
The reaction of a compound of formula XI with N-(1-cyclopenten-1-yl)-morpholine of formula XII to form a compound of formula XIII can be carried out in a suitable solvent such as petroleum ether, ligroin, cyclohexane, hexane, pentane, acetonitrile or dichloromethane at a temperature of between room temperature and the boiling point of the solvent.
The reaction of a compound of formula XIII with hydrazine or hydrazine hydrate can be carried out in a suitable solvent such as methanol, ethanol or tetrahydrofuran at a temperature of between room temperature and the boiling point of the solvent.
Process Variant f)
The reaction of a compound of formula XIV with a compound of formula XV to form a compound of formula I can be carried out analogously to what is described in J. Heterocyclic Chem. 34, 1549 (1997).
The 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of formula II is new and can be obtained according to the methods that are described in the literature, e.g., from cyclopentanone thiosemicarbazone (J. Heterocyclic Chem. 34, 1549 (1997)) or from cyclopentanone-2-carbonitrile (J. Org. Chem., 52, 5538 (1987)).
Subjects of this invention are thus also compounds of general formula II, 
in which R2, R3, R4, R5, R6 and R7 have the meanings that are indicated in general formula I, as valuable intermediate products for the production of the compounds of general formula I according to the invention.
The compounds of formulas III, V, VII, VIII, X, XI, XII, XIV and XV are either commercially available or can be produced according to methods that are known in the literature.
The compounds of formula I and the precursors for their production that are bonded to the solid phase can be produced according to methods that are known in the art. Also, the cleavage can be performed by acid hydrolysis to form the free compounds according to the known methods.
The compounds according to the invention essentially inhibit cyclin-dependent kinases, upon which their action is based, for example, against cancer, such as solid tumors and leukemia; auto-immune diseases, such as psoriasis, alopecia and multiple sclerosis; chemotherapy agent-induced alopecia and mucositis; cardiovascular diseases, such as stenoses, arterioscleroses and restenoses; infectious diseases, such as, e.g., those caused by unicellular parasites, such as trypanosoma, toxoplasma or plasmodium, or those caused by fungi; nephrological diseases, such as, e.g., glomerulonephritis; chronic neurodegenerative diseases, such as Huntington""s disease, amyotrophic lateral sclerosis, Parkinson""s disease, AIDS dementia and Alzheimer""s disease; acute neurodegenerative diseases, such as ischemias of the brain and neurotraumas; viral infections, such as, e.g., cytomegalic infections, herpes, Hepatitis B and C, and HIV diseases.
This invention thus also relates to the use of compounds according to the invention in these indications.